Lymphocyte Subpopulations, Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

Abstract

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-beta. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-beta acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-alpha (CD25) on CD3+ T cells, CD19+ B cells, foetal-type gamma(delta)+CD3+ T cells and foetal-type CD5+CD19+ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-beta1b (BETAFERON, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n = 8) with application of 8 Mill. units IFN-beta1 b every other day, and (2) placebo group (n = 4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-beta has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-beta therapy is warranted.

Dopaminergic Modulation of CD4+CD25^high Regulatory T Lymphocytes in Multiple Sclerosis Patients during Interferon-β Therapy

“…Nonetheless, in our patients the main immune effects of IFN-β were as expected. Indeed, the proliferative response of Teff after 12 months of IFN-β treatment was impaired, and the increased frequency of CD4+CD25 medium T cells observed in patients at baseline, which is a frequent immunological abnormality occurring in MS patients and indicates CD4+ Th1 lymphocyte activation [41,42,43], was significantly reduced, even if not completely reverted, after 12 months of treatment with IFN-β, in agreement with previous reports [41,44]. …”

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

“…In responders, selective induction of TRAIL (22) and other proapoptotic genes in monocytes in response to IFN-β may contribute to the immediate induction of apoptosis in monocytes (9) or may prime monocytes to undergo programmed cell death later, when they differentiate into macrophages during migration across the blood-brain barrier (23). Likewise, the induction of TRAIL, observed on the granulocytes of all the patients with RRMS we have studied, may contribute to the observed apoptosis of granulocytes of patients with MS after IFN-β treatment (24). Remarkably, the protective effect of IFN-α/β in experimental autoimmune encephalomyelitis, the animal model for MS, depends entirely on the response of myeloid cells, because the deletion of IFNAR on myeloid cells, but not on other cells, increases disease burden during the effector phase of CNS autoimmunity, through enhanced macrophage invasion, cytokine/ chemokine production, and demyelination (25).…”

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes

“…Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune disease associated with dysregulation of adaptive immunity, leading to the periodic entry of immune cells into the central nervous system (CNS) and subsequent tissue damage with symptoms of neurological dysfunction. Among a number of different pathological disease mechanisms, an imbalance in the oxidative environment has also been described 2,3 .…”